JP2002212076A - Prophylactic or therapeutic agent for diabetes comprising condensed heterocyclic compound or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a prophylactic or a therapeutic agent for diabetes comprising a specific condensed heterocyclic compound or its salt as an active ingredient. SOLUTION: This prophylactic or therapeutic agent for the diabetes comprises the condensed heterocyclic compound represented by the formula (I') [wherein, G is CN, NO2, CO2R4, CHO, SO2NRaRb or CONRaRb; R1 is a halogen atom, an O-R5 group or an S-R5 group; R2 is a halogen atom, an O-R5 group (wherein, R5 is as described above) or amino group which may be substituted; R8 and R10 are each individually hydrogen atom, a halogen atom or an alkyl group] or its salt as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a preventive or therapeutic drug for diabetes containing a specific fused heterocyclic compound or a salt thereof as an active ingredient. In addition, some of the condensed heterocyclic compounds described below or salts thereof are novel substances. The preventive or therapeutic drug for diabetes of the present invention has a glucose uptake promoting action and a hypoglycemic action, and has diabetes; impaired glucose tolerance; hyperlipidemia, vascular disorder, retinopathy, nephropathy, neuropathy, hypertension, etc. associated with diabetes. It is useful as a prophylactic or therapeutic agent for various complications; and obesity.

[0002]

2. Description of the Related Art Generally, insulin preparations and oral hypoglycemic agents are mainly used as antidiabetic agents having hypoglycemic action. Oral hypoglycemic agents include insulin secretagogues represented by sulfonylurea agents, hepatic gluconeogenesis inhibitors represented by biquanide agents, and insulin sensitizers represented by thiazolidine derivatives. However, there are many patients in which these therapeutic agents do not work effectively, and it is not easy to control blood sugar with these therapeutic agents alone, and at present, various diabetic complications are caused. Among the peripheral tissues in the body, muscle is the most important tissue responsible for glucose processing when blood glucose rises, and the decrease in glucose uptake of muscle cells is one of the major causes of hyperglycemia in diabetic patients. It is considered. Antidiabetic drugs whose main effect is to directly promote glucose uptake in muscle tissue without depending on insulin are a new type of hypoglycemic agent, and are disclosed in JP-A-6-345647 and JP-A-8-345.
Although the one described in 12579 has been proposed, it has not been put to practical use. Both publications describe that it takes 24 hours to treat a test compound to a muscle cell, but does not describe the expression of the effect when treated for about 1 hour. The present inventors have found that by treating a muscle cell with a compound represented by the following formula (I) having a structure completely different from those described in both publications for a short time, a sugar uptake promoting effect is exhibited. . In addition, it was confirmed that the compound of formula (I) described below exhibited a hypoglycemic effect and an ameliorating effect on abnormal glucose tolerance in several hours after administration of the compound to KK-Ay mice and the like, which are diabetes disease state models.

Compounds having a chemical structure similar to the compound of the formula (I) described later include WO 97/35550 and WO 99/6.
0858 and WO00 / 44754. However, these publications do not describe the action as a sugar uptake promoter into muscle cells.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have found that when a specific fused heterocyclic compound or a salt thereof is treated for a short period of time on muscle cells, it exerts an action of promoting sugar uptake, and proposes the present invention. Reached.

[0005]

Means for Solving the Problems The present inventors have conducted various studies in order to find a better therapeutic agent for diabetes, and as a result, completed the present invention. That is, the present invention provides a compound represented by the formula (I):

[0006]

Embedded image Wherein A is a nitrogen atom or C—GＣG is CN, NO ₂ ,
SO ₂ R ³ (R ³ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group , An optionally substituted aryl group or an optionally substituted heterocyclic group), CO ₂ R ⁴
(R ⁴ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, An optionally substituted aryl group or an optionally substituted heterocyclic group), CH
O, SO ₂ NR ^a R ^b (R ^a and R ^b are each independently
A hydrogen atom, a hydroxyl group, an alkoxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, An optionally substituted aryl group or an optionally substituted heterocyclic group, or R ^a and R ^b together form a ring)
R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, or a substituted CONR ^a R ^b (R ^a and R ^b are as defined above). A good alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, -B ¹ —R ⁵ group (B ¹ is CO, COO, O, OCO, OSO ₂ , S, SO or SO ₂ , and R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group An optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group). Amino group or -N = CR ⁶ R ⁷
(R ⁶ and R ⁷ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group,
An optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group,
Y and Z are each independently an aryl group or an optionally substituted heterocyclic group);
A nitrogen atom or C—R ⁸ (R ⁸ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group , optionally substituted cycloalkenyl be group, an optionally substituted aryl group, an optionally substituted heterocyclic group, -B ² -R ⁹ group (B ² is CO, COO,
O, OCO, OSO ₂ , S, SO or SO ₂ ;
⁹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, An aryl group which may be substituted or a heterocyclic group which may be substituted), an amino group which may be substituted, a cyano group or a nitro group), and when Y and Z simultaneously take CR- ⁸ , 2 R ⁸ may be the same or different; X is a nitrogen atom or C-
R ¹⁰ (R ¹⁰ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted Good cycloalkenyl group, -B
^{A 2-} R ⁹ group (B ² and R ⁹ are as defined above), an optionally substituted amino group, a cyano group or a nitro group)
And when Y is CR ⁸ and X is CR ¹⁰ or Z is CR ⁸ , does R ⁸ and R ¹⁰ or two R ⁸ together comprise a heteroatom? Or a salt thereof may be formed without forming a condensed heterocyclic compound or a salt thereof as an active ingredient.

The salt of the fused heterocyclic compound of the formula (I) is
Any pharmaceutically acceptable salt may be used, for example, hydrochloride,
Mineral acid salts such as sulfates and nitrates; organic acid salts such as p-toluenesulfonic acid salt, propanesulfonic acid salt and methanesulfonic acid salt; alkali metal salts such as potassium salt and sodium salt; Alkaline earth metal salts; organic amine salts such as triethanolamine salts and tris (hydroxymethyl) aminomethane salts. Some of these salts have water of crystallization.

In the formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
The alkyl part of the optionally substituted alkyl group represented by R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a and R ^b generally has 1 to 18 carbon atoms, for example, a methyl group, Ethyl group, propyl group, butyl group, pentyl group, hexyl group,
Examples thereof include an octyl group, a nonyl group, a decyl group, and a nonadecyl group, and these include those having a linear or branched fatty chain with structural isomerism.

In the formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
The alkenyl part of the optionally substituted alkenyl group represented by R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a and R ^b , and the alkynyl part of the optionally substituted alkynyl group are generally Examples thereof include those having 2 to 18 carbon atoms, including those having structural isomers of linear or branched fatty chains.

In the formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
The cycloalkyl portion of the optionally substituted cycloalkyl group represented by R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a and R ^b , and the cycloalkenyl portion of the optionally substituted cycloalkenyl group Examples thereof include those having generally 3 to 10 carbon atoms, and monocyclic groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclopentenyl group, and a cyclohexenyl group, and a condensed polycyclic group. And a cross-linked polycyclic group.

In the formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
As the aryl moiety of the optionally substituted aryl group represented by R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^a and R ^b , in addition to a phenyl group, a condensed polycyclic group such as a naphthyl group Is mentioned.

In the formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
The heterocyclic moiety of the optionally substituted heterocyclic group represented by R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^a and R ^b includes a pyrrolyl group,
Pyrrolinyl group, pyrrolidinyl group, furanyl group, dihydrofuranyl group, tetrahydrofuranyl group, thienyl group, dihydrothienyl group, tetrahydrothienyl group, pyrazolyl group, pyrazolinyl group, pyrazolidinyl group, imidazolyl group, imidazolinyl group, imidazolidinyl group, oxazolyl group, Oxazolinyl group, oxazolidinyl group, isoxazolyl group, isoxazolinyl group, isoxazolidinyl group, thiazolyl group, thiazolinyl group, thiazolidinyl group, isothiazolyl group, isothiazolinyl group,
Isothiazolidinyl group, oxadiazolyl group, oxadiazolinyl group, oxadiazolidinyl group, thiadiazolyl group, thiadiazolinyl group, thiadiazolidinyl group, triazolyl group, triazolinyl group, triazolidinyl group, tetrazolyl group, tetrazolinyl group, tetrazolidinyl group , Dioxolyl, dioxolanyl, dithiolyl, dithiolanyl, pyridyl, dihydropyridyl, tetrahydropyridyl, piperidinyl, pyrimidyl, dihydropyrimidyl, tetrahydropyrimidyl, hexahydropyrimidyl, pyridazinyl Group, dihydropyridazinyl group, tetrahydropyridazinyl group,
Hexahydropyridazinyl, pyrazinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, dioxinyl, dioxenyl, dioxanyl, dithianyl , A monocyclic heterocyclic group such as a morpholinyl group; a thienothienyl group, a dihydrocyclopentathienyl group, an indolyl group, a tetrahydroindolyl group,
Isoindolyl group, tetrahydroisoindolyl group, benzothienyl group, tetrahydrobenzothienyl group, benzofuranyl group, tetrahydrobenzofuranyl group, benzooxazolyl group, tetrahydrobenzoxazolyl group,
Benzoisoxazolyl group, tetrahydrobenzoisoxazolyl group, benzothiazolyl group, tetrahydrobenzothiazolyl group, benzoisothiazolyl group, tetrahydrobenzoisothiazolyl group, benzimidazolyl group, tetrahydrobenzimidazolyl group, benzodioxolyl group Benzodithiolyl group, benzodioxanyl group, benzodithianyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, condensed polycyclic heterocyclic group such as purinyl group; quinuclidinyl group and the like Such a crosslinked polycyclic heterocyclic group is exemplified.

In the formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
Secondary of an optionally substituted alkyl group, an optionally substituted alkenyl group and an optionally substituted alkynyl group represented by R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a and R ^b Examples of the substituent include a halogen atom, a hydroxyl group, a mercapto group, a substituted alkoxy group, a substituted alkylthio group, a substituted alkenyloxy group, a substituted alkenylthio group, a substituted alkynyloxy group, a substituted alkynylthio group, a substituted cycloalkyl group. Alkyl group, substituted cycloalkenyl group, substituted cycloalkoxy group, substituted cycloalkylthio group, substituted cycloalkenyloxy group, substituted cycloalkenylthio group, substituted alkoxycarbonyl group, substituted alkylcarbonyl group, substituted alkyl Carbonyloxy group, substituted alkenyloxycarbonyl group, substituted alkenylcarbonyl group A substitutable alkenylcarbonyl group, a substitutable alkynyloxy group, a substitutable alkynyl group, a substitutable alkynyloxy carbonyl group,
Substituted cycloalkoxycarbonyl group, substituted cycloalkylcarbonyl group, substituted cycloalkylcarbonyloxy group, substituted cycloalkenyloxycarbonyl group, substituted cycloalkenylcarbonyl group, substituted cycloalkenylcarbonyloxy group, substituted aryl group,
Substituted aryloxy group, substituted arylthio group, substituted aryloxycarbonyl group, substituted arylcarbonyl group, substituted arylcarbonyloxy group, substituted heterocyclic group, substituted heterocyclic oxy group, substituted heterocyclic thio group ,
Substituted heterocyclic oxycarbonyl group, substituted heterocyclic carbonyl group, substituted heterocyclic carbonyloxy group, substituted amino group, cyano group, nitro group, carboxyl group, substituted aminocarbonyl group, substituted alkylsulfonyl group, substituted Alkenylsulfonyl groups, substituted alkynylsulfonyl groups, substituted cycloalkylsulfonyl groups, substituted cycloalkenylsulfonyl groups, substituted arylsulfonyl groups, substituted heterocyclic sulfonyl groups, substituted aminosulfonyl groups, and substituted aminosulfonyl groups. The number of groups may be one or two or more. When the number of substituents is two or more, those substituents may be the same or different.

In the formula (I), R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
An optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group represented by R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a and R ^b; As the secondary substituent of the heterocyclic group which may be substituted, a halogen atom, a hydroxyl group, a mercapto group, a substitutable alkyl group,
Substituted alkenyl group, substituted alkynyl group, substituted alkoxy group, substituted alkylthio group, substituted alkenyloxy group, substituted alkenylthio group, substituted alkynyloxy group, substituted alkynylthio group, substituted cycloalkyl group, Substituted cycloalkenyl group, substituted cycloalkoxy group, substituted cycloalkylthio group, substituted cycloalkenyloxy group, substituted cycloalkenylthio group, substituted alkoxycarbonyl group, substituted alkylcarbonyl group, substituted alkylcarbonyloxy group , Substituted alkenyloxycarbonyl group, substituted alkenylcarbonyloxy group, substituted alkenylcarbonyloxy group, substituted alkynyloxycarbonyl group, substituted alkynylcarbonyl group, substituted alkynylcarbonyloxy group, substituted cycloalkoxy Rubonyl group, substituted cycloalkylcarbonyl group, substituted cycloalkylcarbonyloxy group, substituted cycloalkenyloxycarbonyl group, substituted cycloalkenylcarbonyl group, substituted cycloalkenylcarbonyloxy group, substituted aryl group, substituted aryloxy Group, a substituted arylthio group, a substituted aryloxycarbonyl group, a substituted arylcarbonyl group,
A substituted arylcarbonyloxy group, a substituted heterocyclic group,
Substituted heterocyclic oxy group, substituted heterocyclic thio group, substituted heterocyclic oxycarbonyl group, substituted heterocyclic carbonyl group,
Substituted heterocyclic carbonyloxy group, substituted amino group, cyano group, nitro group, carboxyl group, substituted aminocarbonyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkynylsulfonyl group, substituted cycloalkyl Examples thereof include a sulfonyl group, a substitutable cycloalkenylsulfonyl group, a substitutable arylsulfonyl group, a substitutable heterocyclic sulfonyl group, a substitutable aminosulfonyl group, and the like. If the number of substituents is 2 or more,
These substituents may be the same or different.

The secondary substituent of the optionally substituted amino group represented by R ¹ , R ² , R ⁸ and R ¹⁰ in the formula (I) includes a hydroxyl group, a substitutable alkyl group and a substitutable alkenyl group. ,
A substitutable alkynyl group, a substitutable alkoxy group, a substitutable alkenyloxy group, a substitutable alkynyloxy group, a substitutable cycloalkyl group, a substitutable cycloalkenyl group, a substitutable cycloalkoxy group, a substitutable cycloalkenyloxy group,
Substituted alkoxycarbonyl group, substituted alkylcarbonyl group, substituted alkenyloxycarbonyl group, substituted alkenylcarbonyl group, substituted alkynyloxycarbonyl group, substituted alkynylcarbonyl group, substituted cycloalkoxycarbonyl group, substituted cycloalkylcarbonyl Group, substituted cycloalkenyloxycarbonyl group, substituted cycloalkenylcarbonyl group, substituted aryl group, substituted aryloxy group, substituted aryloxycarbonyl group, substituted arylcarbonyl group, substituted heterocyclic group, substituted heterocyclic group Ring oxy group, substituted heterocyclic oxycarbonyl group, substituted heterocyclic carbonyl group, substituted aminocarbonyl group, substituted alkylsulfonyl group, substituted alkenylsulfonyl group, substituted alkynylsulfonyl group, substituted cycloalkyl group And a substitutable cycloalkenylsulfonyl group, a substitutable arylsulfonyl group, a substitutable heterocyclic sulfonyl group, a substitutable aminosulfonyl group, and the like. And in the case of two, they may be the same or different. Also, two secondary substituents may together form a ring with or without a heteroatom.

Of the above secondary substituents, the tertiary substituent of each substitutable group includes a halogen atom, a hydroxyl group, a mercapto group, a cyano group, a nitro group, a carboxyl group, an amino group, an alkyl group, an alkenyl group, Alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group, heterocyclic oxy group, alkylthio group , Alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, arylthio, heterocyclic thio, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, arylsulfonyl , Heterocyclic sulfonyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heterocyclic carbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl Group, cycloalkyloxycarbonyl group, cycloalkenyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group,
Alkenylaminocarbonyl group, alkynylaminocarbonyl group, cycloalkylaminocarbonyl group, cycloalkenylaminocarbonyl group, arylaminocarbonyl group, heterocyclic aminocarbonyl group, aminosulfonyl group, alkylaminosulfonyl group, dialkylaminosulfonyl group, alkenylaminosulfonyl Group, alkynylaminosulfonyl group, cycloalkylaminosulfonyl group, cycloalkenylaminosulfonyl group, arylaminosulfonyl group, heterocyclic aminosulfonyl group, alkylamino group, dialkylamino group, alkenylamino group, alkynylamino group, cycloalkylamino group A cycloalkenylamino group, an arylamino group, a heterocyclic amino group, an alkylcarbonylamino group, an alkenylcarbonylamino group, Rukinylcarbonylamino group, cycloalkylcarbonylamino group, cycloalkenylcarbonylamino group, arylcarbonylamino group, heterocyclic carbonylamino group, alkylsulfonylamino group, alkenylsulfonylamino group, alkynylsulfonylamino group, cycloalkylsulfonylamino group, Examples thereof include a cycloalkenylsulfonylamino group, an arylsulfonylamino group, and a heterocyclic sulfonylamino group. The number of the tertiary substituents may be one or two or more. The substituents may be the same or different. Further, when the secondary substituent is an amino group substituted by two tertiary substituents, the tertiary substituents may together form a ring with or without a hetero atom.

Also, the alkyl moiety of these tertiary substituents,
The alkenyl portion, alkynyl portion, cycloalkyl portion, cycloalkenyl portion, aryl portion, and heterocyclic portion further include a halogen atom, a hydroxyl group, a mercapto group, a cyano group, a nitro group, a carboxyl group, an amino group, an alkyl group, a haloalkyl group, and an alkoxy group. Group, haloalkoxy group, alkylthio group, haloalkylthio group, alkoxycarbonyl group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, aminosulfonyl group, alkylaminosulfonyl group, dialkylaminosulfonyl group, alkylamino group, It may be substituted with a quaternary substituent such as a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group, a cycloalkyl group, an aryl group, a heterocyclic group, and the number of such substituents is one. And it may be two or more than,
When the number of substituents is two or more, those substituents may be the same or different.

Among the condensed heterocyclic compounds of the formula (I) or salts thereof, the compounds of the formula (I '):

Embedded image

[Wherein G is CN, NO_Two, CO_TwoR^Four(R^Four
Is a hydrogen atom, an alkyl group which may be substituted,
Alkenyl group, alkynyl which may be substituted
Group, optionally substituted cycloalkyl group, optionally substituted
Good cycloalkenyl group, aryl group which may be substituted
Or an optionally substituted heterocyclic group), CHO, S
O _TwoNR^aR^b(R^aAnd R^bAre each independently a hydrogen source
, Hydroxyl group, alkoxy group, alkyl which may be substituted
Group, an optionally substituted alkenyl group, an optionally substituted
Alkynyl group, cycloalkyl group which may be substituted,
Optionally substituted cycloalkenyl group, optionally substituted
An aryl group or a heterocyclic group which may be substituted;
Or R^aAnd R^bTogether form a ring) or
CONR^aR^b(R^aAnd R^bIs as described above)
R;¹Is a halogen atom, -OR^FiveGroup (R^FiveIs a hydrogen source
, An optionally substituted alkyl group, an optionally substituted
Alkenyl group, optionally substituted alkynyl group, substituted
Cycloalkyl group, cycloalkyl which may be substituted
Alkenyl, optionally substituted aryl or substituted
Or -SR.^FiveGroup (R^FiveIs
R is as described above);^TwoIs a halogen atom, -O
-R^FiveGroup (R^FiveIs as described above) or even if substituted
A good amino group; R⁸And R^TenAre independent
Is a hydrogen atom, a halogen atom or an alkyl group]
The fused heterocyclic compound represented by the formula or a salt thereof is a novel compound
It is.

[0020]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Some preferred embodiments of the present invention will now be described, but the present invention is not limited thereto.

The compound of the above formula (I) and the compound of the formula (I ') included therein are useful as active ingredients of a preventive or therapeutic agent for diabetes, and are useful as drugs listed below, for example. It is. (1) An agent for promoting sugar uptake into muscle cells. (2) hypoglycemic agents. (3) A preventive or therapeutic drug for impaired glucose tolerance. (4) A drug for preventing or treating complications associated with diabetes. (5) A prophylactic or therapeutic agent for at least one complication associated with diabetes selected from the group consisting of hyperlipidemia, vascular disorder, retinopathy, nephropathy, neuropathy and hypertension. (6) An agent for preventing or treating obesity.

Among the compounds of the above-mentioned formula (I), the following compounds are excellent as active ingredients for drugs for preventing or treating diabetes. (1) A is CG ｛G is CN, NO ₂ , CO ₂ R ⁴ (R
⁴ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, An aryl group or an optionally substituted heterocyclic group), CHO, S
O ₂ NR ^a R ^b (R ^a and R ^b each independently represent a hydrogen atom, a hydroxyl group, an alkoxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, A cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, or R ^a and R ^b together form a ring to) or CONR ^a R ^b (R a and R ^b is an a is)} as described above; Y and Z are each independently a nitrogen atom or C
-R ⁸ ｛R ⁸ represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, A cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group,
—B ² —R ⁹ groups (B ² is CO, COO, O, OCO, OS
O ₂ , S, SO or SO ₂ , wherein R ⁹ is a hydrogen atom,
An optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or An optionally substituted heterocyclic group), an optionally substituted amino group,
R is a cyano group or a nitro group, and when Y and Z simultaneously take C—R ⁸ , two R ⁸ may be the same or different; X is a nitrogen atom or C—R ¹⁰ ｛R ¹⁰ is A hydrogen atom, a halogen atom, an alkyl group which may be substituted,
An optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, a -B ² -R ⁹ group (B ² and R ⁹ are as defined above. As described above), which is an amino group, a cyano group or a nitro group which may be substituted.

(2) R ¹ and R ² are each independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group,
Optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, -B 1 ^{'-R 5} group (B ^1' is O or is S, R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyl An alkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group), an optionally substituted amino group or -N = CR ⁶ R ⁷
(R ⁶ and R ⁷ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group,
An optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group,
An optionally substituted aryl group or an optionally substituted heterocyclic group);
A nitrogen atom or C—R ⁸ ｛R ⁸ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group , optionally substituted cycloalkenyl be group, an optionally substituted aryl group, an optionally substituted heterocyclic group, -B 2 ^{'-R 9} group (B ^2' is CO, CO
O, O, OCO, S, and R ⁹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, A cycloalkylenyl group which may be substituted, an aryl group which may be substituted or a heterocyclic group which may be substituted), an amino group which may be substituted, a cyano group or a nitro group.

Among the compounds of the formula (I), the compounds of the formula (I ') are more excellent as active ingredients for drugs for preventing or treating diabetes. In addition, the pharmaceutical composition containing the compound of Formula (I ') has not been known hitherto. Among the compounds of formula (I '), more desirable compounds are listed below.

(I) A compound of the formula (I ′) wherein R ² is an optionally substituted amino group. (Ii) The compound of the formula (I ′), wherein R ² is an optionally substituted amino group, and R ⁸ and R ¹⁰ are hydrogen atoms. (Iii) the optionally substituted amino group represented by R ² is-
NR ^c R ^d group wherein R ^c and R ^d are each independently a hydrogen atom, —OR ⁵ group (wherein R ⁵ is a hydrogen atom, an optionally substituted alkyl group, Good alkenyl groups,
An optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group,
An optionally substituted aryl group or an optionally substituted heterocyclic group), an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cyclo An alkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, or R
The compound of (ii), wherein ^c and R ^d together form a ring.

(Iv) G is CN, CO_TwoR^Four(R^FourIs hydrogen
Atom, alkyl group which may be substituted, which may be substituted
Alkenyl group, alkynyl group which may be substituted,
Cycloalkyl group which may be substituted, cyclo which may be substituted
Alkenyl group, aryl group which may be substituted or substituted
Which may be a heterocyclic group), CHO, SO_TwoNR^aR
^b(R^aAnd R^bAre each independently a hydrogen atom, hydroxyl
Group, alkoxy group, alkyl group which may be substituted, substitution
Alkenyl group, alkynyl which may be substituted
Group, an optionally substituted cycloalkyl group,
A cycloalkenyl group which may be substituted,
A ring group or R^aAnd R^bTogether
To form) or CONR^{a '}R^{b '}(R^{a '}And R^{b '}
Are each independently a hydroxyl group, an alkoxy group,
Alkyl group, alkenyl group which may be substituted,
Alkynyl group which may be substituted, cyclo which may be substituted
Alkyl group, cycloalkenyl group which may be substituted,
Optionally substituted aryl group or optionally substituted hetero group
A ring group or R^{a '}And R^{b '}Ring together
A compound of formula (I ′) (V) G is CN, NO_Two, CO_TwoR^Four(R^FourIs a hydrogen atom,
Optionally substituted alkyl group, optionally substituted alk
Nil group, alkynyl group which may be substituted,
Good cycloalkyl group, optionally substituted cycloalkene
Nyl group, optionally substituted aryl group or substituted
CHO, C-SO_TwoNR^aR^b
(R^aAnd R^bAre each independently a hydrogen atom, a hydroxyl group,
Alkoxy group, optionally substituted alkyl group, substituted
Alkenyl group, alkynyl which may be substituted
Group, optionally substituted cycloalkyl group, optionally substituted
A good cycloalkenyl group or an optionally substituted heterocyclic group
A ring group or R^aAnd R^bTogether form a ring
Or CONR^{a '}R^{b '}(R^{a '}And R^{b '}Is
Each independently a hydroxyl group, an alkoxy group,
A good alkyl group, an optionally substituted alkenyl group,
Alkynyl group, cycloalkyl which may be substituted
Alkyl group, optionally substituted cycloalkenyl group, substituted
Aryl group or heterocyclic ring which may be substituted
Is a group or R^{a '}And R^{b '}Together
To form); R¹Is -OR^FiveGroup (R^FiveIs a hydrogen source
, An optionally substituted alkyl group, an optionally substituted
Alkenyl group, optionally substituted alkynyl group, substituted
Cycloalkyl group, cycloalkyl which may be substituted
Alkenyl, optionally substituted aryl or substituted
Or -SR.^FiveGroup (R
^FiveIs an alkyl group which may be substituted, may be substituted
Alkenyl group, alkynyl group which may be substituted,
Cycloalkyl group which may be substituted, cyclo which may be substituted
Alkenyl group, aryl group which may be substituted or substituted
Which is a heterocyclic group which may be
object.

In the —NR ^c R ^d group of the above (iii), R ^c and R
an alkyl group which may be substituted in each substituent represented by ^d , an alkenyl group which may be substituted, an alkynyl group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkenyl which may be substituted Group, an optionally substituted aryl group or an optionally substituted heterocyclic group are defined as
The same as defined for each substituent in the compound of the formula (I). Among the -NR ^c R ^d groups, a substituted alkylamino group, a substituted dialkylamino group, an alkylcarbonylamino group, a substituted alkynylamino group, a cycloalkylamino group, a substituted arylamino group are desirable, and Alkylamino groups or displaceable arylamino groups are more desirable. Examples of the displaceable alkylamino group include a benzylamino group, a 4-nitrobenzylamino group, a 4-pyridylmethylamino group, a 3-pyridylmethylamino group,
-Pyridylmethylamino group, dioxolanylmethylamino group, pyranylmethylamino group, methylamino group, ethylamino group, dimethylamino group and the like. Examples of the substitutable arylamino group include a phenylamino group,
Cyanophenylamino group, 3-cyanophenylamino group, 4-chlorophenylamino group, 2-chlorophenylamino group, 4-methylphenylamino group, 3-methylphenylamino group, 2-methylphenylamino group, 4-nitrophenylamino Group, 3-nitrophenylamino group and the like.

The preventive or therapeutic drug for diabetes of the present invention is usually used in the form of a general pharmaceutical preparation. This pharmaceutical formulation contains commonly used fillers, extenders, binders, humectants,
It is prepared using diluents or excipients such as disintegrants, surfactants and lubricants. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment. Tablets, pills, powders, powders, granules, capsules, suppositories, solutions, suspensions, emulsions, injections (solutions, suspensions) Etc.), spray, aerosol, cream, ointment, lotion, transdermal (patch, matrix, tape) and the like.

In the form of tablets, those known in the art can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose,
Binders such as potassium phosphate and polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc. Disintegrants, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, humectants such as starch, starch, lactose, kaolin,
Examples thereof include adsorbents such as bentonite and colloidal silicic acid, and lubricants such as purified talc, stearates, powdered boric acid, and polyethylene glycol. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets.

In the form of pills, carriers conventionally known in the art can be widely used as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and the like; Examples thereof include rubber powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrants such as laminaran agar.

For shaping in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. it can.

When prepared as an injection, a liquid preparation,
Emulsions and suspensions are preferably sterilized and isotonic with blood. In forming these solutions, emulsions and suspensions, all diluents commonly used in this field are used. Examples thereof include water, aqueous lactic acid, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. may be added. You may. If necessary, colorants, preservatives, fragrances, flavors,
Sweeteners and other pharmaceuticals may be included in the pharmaceutical formulation.

The amount of the compound of formula (I) to be contained in the antidiabetic agent of the present invention is not particularly limited and may be appropriately selected in a wide range. In a preferred embodiment, the content is 5 to 50% by weight.

The method of administering the preventive or therapeutic drug for diabetes of the present invention is not particularly limited, and is orally or parenterally administered by a method according to various preparation forms, patient age, gender and other conditions, degree of disease and the like. Is administered. For example, when administered orally, tablets, pills, solutions, suspensions, emulsions, granules, capsules and the like are mentioned as desirable embodiments. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, pulmonary, suppository and the like. In the case of an injection, it is preferably administered intravenously, alone or as a mixture with a normal replenisher such as glucose and amino acids, and, if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. It is an aspect. In the case of suppositories, it is a desirable embodiment to administer rectally.

The dose of the drug for preventing or treating diabetes of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, the degree of the disease and the like. The amount is about 0.0 per kg of body weight per day
The dose is preferably 5 to 50 mg, which can be administered once or in several divided doses. It is a desirable embodiment that the dosage unit form contains 1 to 1000 mg of the active ingredient.

The compound of the formula (I) or a salt thereof can be produced by a known method for producing a similar compound or a method analogous thereto. Preferred embodiments include the following methods [1] to [5]. .

[1] Production method 1 formula (II):

Embedded image Wherein R is R ¹ or R ² in formula (I), A is as described above, D is a cyano group or an alkoxycarbonyl group, and L is a leaving group. And a compound of formula (III):

[0038]

Embedded image Wherein X, Y and Z are as defined above, thereby producing the compound of formula (I). In the formula (II), examples of the leaving group represented by L include various ones, and a halogen atom, an —OR ⁵ group, a —SR ⁵ group, or a dialkylamino group is preferable (R ⁵ is as described above). Is).

The reaction of Production Method 1 can be carried out in the presence of a suitable solvent. Specific examples of the solvent include alcohols such as methanol, ethanol, propanol and butanol; aromatic hydrocarbons such as benzene, toluene and xylene; pentane, hexane, heptane, petroleum ether, ligroin, petroleum benzine and the like. Aliphatic hydrocarbons; ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile and propionitrile; acid amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethyl sulfoxide Sulfones such as sulfolane; phosphoric amides such as hexamethylphosphoramide; halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride, and 1,2-dichloroethane And it can be mixtures of these solvents.

In the production method 1, it may be desirable to carry out the reaction in the presence of a base. Specific examples of the base used include triethylamine, pyridine, piperidine, N
-Methylmorpholine, 1,8-diazabicyclo [5,
Organic bases such as 4,0] -7-undecene and N, N-dimethylaniline; alkali metals such as lithium, sodium and potassium; carbonates of alkali metals such as lithium carbonate, sodium carbonate and potassium carbonate; lithium hydrogen carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride;
n-butyllithium, lithium diisopropylamide,
Sodium amide and the like can be mentioned. The reaction of Production Method 1 is generally performed at a reaction temperature of 0 to 150 ° C, preferably at a reaction temperature of 10 to 100 ° C. The reaction time is generally between 0.1 and 48 hours. In production method 1,
The compound of the formula (III) can be used in a ratio of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, per 1 mol of the compound of the formula (II).

The various reaction conditions in Production Method 1 can be appropriately combined with each other. Among these reaction conditions, there are those having a normal range of reaction conditions and a desirable range of reaction conditions.
Can be combined.

[2] Production Method 2 Formula (I-1):

Embedded image Wherein ^one of R ^{1 ′ and} R ^{2 ′} is an amino group, O
H or SH; the other is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, Optionally substituted cycloalkenyl group, optionally substituted aryl group, optionally substituted heterocyclic group, -B ¹ -R ⁵ group (B ¹ and R ⁵ are as defined above), optionally substituted Amino group or -N =
Wherein A, X, Y and Z are as defined above, and CR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are as defined above);

Formula (IV): R'-L 'wherein R' is a substituted
Alkyl group which may be substituted, alkenyl which may be substituted
Group, optionally substituted alkynyl group, optionally substituted
Cycloalkyl group, optionally substituted cycloalkenyl
Group, an optionally substituted aryl group, an optionally substituted
A ring group or -B^{1 ''}-R^Five'Group (B^{1 ''}Is CO or SO
_TwoAnd R^Five'Is an alkyl group which may be substituted,
Alkenyl group, alkynyl which may be substituted
Group, an optionally substituted cycloalkyl group,
Cycloalkenyl group, aryl which may be substituted
Group or an optionally substituted heterocyclic group);
L 'is a leaving group].
And producing the compound of the formula (I). What
In the formula (IV), as the leaving group represented by L ′, various
But halogen atom, methanesulfonyl
Oxy group or paratoluenesulfonyloxy group is desired
Good.

The reaction of Production Method 2 can be carried out in the presence of a suitable solvent. Specific examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene;
Aliphatic hydrocarbons such as pentane, hexane, heptane, petroleum ether, ligroin, petroleum benzine; ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, dioxane; nitriles such as acetonitrile and propionitrile; dimethyl Acid amides such as formamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; phosphoric amides such as hexamethylphosphoramide; chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like. Examples thereof include halogenated hydrocarbons and a mixed solvent thereof.

In the production method 2, in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene and N, N-dimethylaniline; lithium, sodium Alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydride and sodium hydride And hydrides of alkali metals such as potassium hydride; and n-butyllithium, lithium diisopropylamide, and sodium amide.

The reaction of the production method 2 is generally carried out at -70 to 200 ° C.
And desirably at a reaction temperature of -10 to 150 ° C. The reaction time is generally between 0.1 and 48 hours.

In the production method 2, the compound of the formula (IV) may be used in a ratio of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, per 1 mol of the compound of the formula (I-1). it can.

The various reaction conditions in Production Method 2 can be appropriately combined with each other. Among these reaction conditions, there are those having a normal range of reaction conditions and a desirable range of reaction conditions.
Can be combined.

[3] Production Method 3 Formula (I-2):

Embedded image [In the formula, ^one of R ^{1 ″ and} R ^{2 ″} is OH, and the other is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, Optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group, optionally substituted heterocyclic group, -B ¹ -R ⁵ group (B ¹ and R ⁵ are as described above), an optionally substituted amino group or —N−CR ⁶ R ⁷
(R ⁶ and R ⁷ are as defined above); A, X,
Y and Z are as defined above], and a halogenating agent, thereby producing the compound of the above formula (I).

Examples of the halogenating agent used in the reaction of Production Method 3 include phosphorus pentachloride, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, and phenylphosphonic dichloride. The amount is 1 to 10 equivalents, preferably 1 to 5 equivalents, per 1 mol of the compound of the formula (I-2).

The reaction of Production Method 3 can be carried out in the presence of a suitable solvent. Specific examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene;
Aliphatic hydrocarbons such as pentane, hexane, heptane, petroleum ether, ligroin, petroleum benzine; ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, dioxane; chloroform, dichloromethane, carbon tetrachloride, 1,2 -Halogenated hydrocarbons such as dichloroethane and the like, and mixed solvents thereof. The reaction is desirably performed in a system without water.

In the production method 3, in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene, and N, N-dimethylaniline. it can.

The reaction of the production method 2 is generally carried out at -30 to 200 ° C.
The reaction is preferably performed at a reaction temperature of 0 to 150 ° C. The reaction time is generally between 0.1 and 48 hours.

The various reaction conditions in Production Method 3 can be appropriately combined with each other. Among these reaction conditions, there are those having a normal range of reaction conditions and a desirable range of reaction conditions.
Can be combined.

[4] Production Method 4 Formula (I-3):

Embedded image [Wherein, ^one of R ^{1 ′ ″ and} R ^{2 ′ ″} is a halogen atom, a —B ^{1 ″} -R ^{5 ″} group (B ^{1 ″} is O, OSO ₂ , S,
Or a SO _2, R 5 ^'' is a substituted an aryl group which may be also an alkyl group or substituted) or dialkylamino group, the other is a hydrogen atom, a halogen atom, optionally substituted Good alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group, optionally substituted A good heterocyclic group, a -B ¹ -R ⁵ group (B ¹ and R ⁵ are as defined above), an optionally substituted amino group or -N = CR ⁶ R ⁷ (R ⁶ and R ⁷ are as defined above) A, X, Y and Z are as defined above]; and a compound represented by the formula:

Formula (V): R ″ -B ′ ″ wherein R ″ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, A cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted or a heterocyclic group which may be substituted, and B ′ ″ represents an amino group, OH, SH
Is reacted with a compound represented by the formula:
A method for producing the compound of formula (I).

The reaction of Production Method 4 can be carried out in the presence of a suitable solvent. Specific examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene;
Aliphatic hydrocarbons such as pentane, hexane, heptane, petroleum ether, ligroin, petroleum benzine; ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, dioxane; nitriles such as acetonitrile and propionitrile; dimethyl Acid amides such as formamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; phosphoric amides such as hexamethylphosphoramide; chloroform, dichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like. Examples thereof include halogenated hydrocarbons and a mixed solvent thereof.

In production method 4, in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene and N, N-dimethylaniline; lithium, sodium Alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydride and sodium hydride And hydrides of alkali metals such as potassium hydride; and n-butyllithium, lithium diisopropylamide, and sodium amide.

The reaction of the production method 4 is generally carried out at -70 to 150 ° C.
And preferably at a reaction temperature of -10 to 100 ° C. The reaction time is generally between 0.1 and 48 hours.

In the production method 4, the compound of the formula (V) is used in a proportion of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, per 1 mol of the compound of the formula (I-3). it can.

The various reaction conditions in Production Method 3 can be combined with one another as appropriate. Among these reaction conditions, there are those having a normal range of reaction conditions and a desirable range of reaction conditions.
Can be combined.

[5] Production method 5 formula (I-4):

Embedded image [Wherein ^one of R ^{1 ″ ″ and} R ^{2 ″ ″} is an amino group, and the other is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl Group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, -B ¹ -R ⁵ groups (B ¹ and R ⁵ are as defined above), an optionally substituted amino group or —N ＝ CR ⁶ R ⁷
(R ⁶ and R ⁷ are as defined above); A, X,
Y and Z are the same as described above];

The compound of the formula (I) is reacted with a compound represented by the formula (VI): R ⁶ R ⁷ C 7O wherein R ⁶ and R ⁷ are as defined above. How to manufacture.

The reaction of Production Method 5 can be carried out in the presence of a suitable solvent. Specific examples of the solvent include alcohols such as methanol, ethanol, propanol and butanol; aromatic hydrocarbons such as benzene, toluene and xylene; pentane, hexane, heptane, petroleum ether, ligroin, petroleum benzine and the like. Aliphatic hydrocarbons; ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran and dioxane; nitriles such as acetonitrile and propionitrile; acid amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethyl sulfoxide Sulfones such as sulfolane; phosphoric amides such as hexamethylphosphoramide; halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride, and 1,2-dichloroethane And it can be mixtures of these solvents.

In Production Method 5, in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene and N, N-dimethylaniline; lithium carbonate, Alkali metal carbonates such as sodium carbonate and potassium carbonate; and alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.

In Production Method 5, in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a dehydrating agent such as molecular sieves. Further, by using an appropriate solvent, water generated by azeotropic distillation can be removed out of the reaction system.

The reaction of Production Method 5 is generally carried out at -30 to 150 ° C.
The reaction is preferably performed at a reaction temperature of 0 to 100 ° C. The reaction time is generally between 0.1 and 48 hours.

In the production method 5, the compound of the formula (VI) may be used in a ratio of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, per 1 mol of the compound of the formula (I-3). it can.

The various reaction conditions in Production Method 5 can be appropriately combined with each other. Among these reaction conditions, there are those having a normal range of reaction conditions and a desirable range of reaction conditions.
Can be combined.

The compound of the formula (I) or a salt thereof can be produced by the production methods described in the above [1] to [5] or a combination thereof.

The compound of the formula (I) can form a salt by a usual method. Further, the compound of the formula (I) may form an inner salt.

Of the compounds of the formula (I) or salts thereof, those having a carboxyl group in the molecular structure or salts thereof can be produced by hydrolyzing the corresponding ester under acid or alkaline conditions. it can.

Among the compounds of the formula (I) or salts thereof, the compounds of the formula (I ') or salts thereof are prepared according to the processes 1 to 3 described above.
According to No. 5, it can be produced by the production methods described in the following [A] to [G] or a combination of these production methods.

[A] Of the compounds of the formula (I ′) or salts thereof, of the formula (I′-1):

Embedded image Wherein R ¹ , R ⁸ , R ¹⁰ and G are as defined in the above formula (I ′), or a salt thereof, represented by the formula (VII)

Embedded image[Wherein, R¹And G are as described above; D is alkoxy.
L is a halogen atom, -OR
^FiveGroup, -SR^FiveOr a dialkylamino group (R ^Five
Is as described above)] and a compound represented by the formula (VII
I):

Embedded image [Wherein R ⁸ and R ¹⁰ are the same as those described above]. In addition,
The production method [A] is based on the production method 1, and the reaction conditions of the production method 1 can be applied.

[B] Among the compounds of formula (I ′) or salts thereof, of formula (I′-2):

Embedded image Wherein R ¹ , R ⁸ and R ¹⁰ are as defined in formula (I ′) above; G ′ is CN, NO ₂ , SO ₂ NR ^a R ^b
(R ^a and R ^b are as described above) or CONR
^a R ^b (R ^a and R ^b are as defined above), or a salt thereof, represented by the formula (VII ′):

Embedded image Wherein R ¹ and G ′ are as described above; L is a halogen atom, —OR ⁵ group, —SR ⁵ group or dialkylamino group (R ⁵ is as defined above). And a compound of formula (VIII):

Embedded image [Wherein R ⁸ and R ¹⁰ are the same as those described above]. In addition,
Production method [B] is based on Production method 1, and the reaction conditions of Production method 1 can be applied.

[C] Among the compounds of formula (I ′) or salts thereof, of formula (I′-3):

Embedded image [Wherein R ¹ , R ⁸ , R ¹⁰ and G are as defined in the above formula (I ′)], or a salt thereof is produced by the method described in production method [A]. Formula (I'-
The compound can be produced by reacting the compound of 1) with a halogenating agent. The production method [C] is based on the production method 3, and the reaction conditions of the production method 3 can be applied.

[D] Of the compounds of formula (I ′) or salts thereof, of formula (I′-4):

Embedded image[Wherein, R¹, R⁸, R¹⁰And G are defined in the above formula (I ').
As defined; R ^Five'Is an optionally substituted al
A kill group, an optionally substituted alkenyl group, an optionally substituted
Good alkynyl group, cycloalkyl which may be substituted
Group, an optionally substituted cycloalkenyl group,
Or an optionally substituted heterocyclic group.
The compound represented by the formula
A compound of the formula (I'-1) produced by the method of formula
(IX): R^Five'-L 'where R^Five'Is as described above.
L ′ is a halogen atom, a methanesulfonyloxy group
Or a paratoluenesulfonyloxy group]
The compound can be produced by reacting the compound with What
Incidentally, the production method [D] is based on the production method 2,
The following reaction conditions can be applied.

[E] Among the compounds of formula (I ′) or salts thereof, of formula (I′-5):

Embedded image Wherein R ¹ , R ⁸ , R ¹⁰ and G are as defined in the above formula (I ′); and Q is a substituted amino group.
A compound represented by the formula (I′-3) and a compound thereof represented by the formula (IV)
-1): by reacting with a compound represented by the formula: HQ wherein Q is a substituted amino group,
Can be manufactured. The production method [E] is based on the production method 4, and the reaction conditions of the production method 4 can be applied.

[F] Further , the compound of the formula (I′-5) or a salt thereof is prepared by mixing the compound of the formula (I′-4) produced by the method described in the production method [D] with the compound of the formula (IV-1) ) Can also be produced by reacting the compound with The production method [F] is based on the production method 4, and the reaction conditions of the production method 4 can be applied.

[G] Further, among the compounds of the formula (I'-5) or salts thereof, the compounds of the formula (I'-5 '):

Embedded image Wherein R ¹ , R ⁸ , R ¹⁰ and Q are as defined in the above formula (I′-5); G ′ is as defined in the above formula (I′-2) The compound represented by the formula (I′-) is prepared by the method described in the production method [B].
2) a compound of the formula (IV-2): L'-J wherein J is the substitution of a substituted amino group represented by Q; L 'is a halogen atom, a methanesulfonyloxy group or Which is a toluenesulfonyloxy group]. The production method [G] is based on the production method 2, and the reaction conditions of the production method 2 can be applied.

[0081]

EXAMPLES Examples (synthesis examples and test examples) according to the present invention will be described below, but the present invention is not limited to these examples.

Synthesis Example 1 7-benzylamino-5-methylthiopyrazolo [1,5-a] pyrimid
Synthesis of Gin-6-carbonitrile (Compound No. 2) (1) Bismethylthiomethylenepropanedinitrile 10.3
g, 3-aminopyrazole (5.0 g) and ethanol (250 ml) were stirred under reflux for about 6 hours, cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals collected by filtration are washed with ethanol, dried, and dried to give 7-amino-5-methylthiopyrazolo [1,5-a] pyrimidine-6-carbonitrile having a melting point of 240 ° C. or higher (compound
No. 1) 10.9 g was obtained. (2) 7-amino-5-methylthiopyrazolo [1,5-a] pyrimidine
To 6 mg of -6-carbonitrile and 8 mL of DMF, 100 mg of sodium hydride (60%) was added, and the mixture was stirred at room temperature for about 10 minutes. Then, 420 mg of benzyl bromide was added, and the mixture was stirred at about 50 ° C for about 2 hours. After completion of the reaction, the mixture was cooled to room temperature, about 50 mL of water was added, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography,
7-benzylamino-5-methylthiopyrazolo [1,5-
a] Pyrimidine-6-carbonitrile (Compound No. 2) 570mg
I got

Synthesis Example 2 7-benzyloxy-5-methylthiopyrazolo [1,5-a] pyrimid
Synthesis of gin-6-carbonitrile (Compound No. 51) (1) 3.0 g of 2-cyano-3,3-bismethylthio-2-propenoic acid methyl ester, 1.3 g of 3-aminopyrazole and 20 ml of ethanol were heated under reflux. After stirring for about 2.5 hours, the mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals collected by filtration are washed with ethanol and dried, and 1.69 g of 7-hydroxy-5-methylthiopyrazolo [1,5-a] pyrimidine-6-carbonitrile (compound No. 49) having a melting point of 250 ° C. or higher is obtained. Obtained. (2) 7-Hydroxy-5-methylthiopyrazolo [1,5-a] pyrimidine-6-carbonitrile 400 mg, 80 mL of sodium hydride (60%) in 6 mL of DMF, and stirred at room temperature for about 10 minutes After that, 350 mg of benzyl bromide was added, and the mixture was stirred at about 50 ° C overnight. After the reaction is completed, cool to room temperature, add about 50 mL of water,
The precipitated crystals were collected by filtration, washed with water, and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography to give 7-benzyloxy-5-methylthiopyrazolo [1,5-a] pyrimidine-6-carbonitrile (compound No. 5) having a melting point of 194 ° C.
1) 490 mg was obtained.

Synthesis Example 3 7- (4-Pyridylmethyl) amino-5-methylthiopyrazolo [1,
5-a] Pyrimidine-6-carbonitrile (Compound No. 3)
Forming (1) 7-hydroxy-5-methyl-thio-pyrazolo [1,5-a] pyrimidine-6-carbonitrile (Compound No.49) 2.15g, N, N-
A mixture of 1.3 g of dimethylaniline and 5 mL of phosphorus oxychloride was stirred under reflux for about 3 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into ice water and stirred. The precipitated crystals were collected by filtration, washed with water, and dried to obtain crude crystals. The crude crystals are purified by silica gel column chromatography, melting point 201-202 ° C.
7-chloro-5-methylthiopyrazolo [1,5-a] pyrimidine-6
2.17 g of carbonitrile (Compound No. 62) was obtained. (2) 7-chloro-5-methylthiopyrazolo [1,5-a] pyrimidine
-6-carbonitrile 950 mg, 4-picolylamine 460 mg, triethylamine 430 m in ice-cooled 20 mL of acetonitrile
g and acetonitrile (1 mL) were added dropwise, and the mixture was stirred for about 1 hour. After completion of the reaction, about 80 mL of water was added, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography, melting point 153-154.
7- (4-pyridylmethyl) amino-5-methylthiopyrazolo [1,5-a] pyrimidine-6-carbonitrile (compound No.
3) 970 mg was obtained.

Synthesis Example 4 7-furfurylamino-5-methylthiopyrazolo [1,5-a] pyri
Synthesis of Midine-6-carbonitrile (Compound No. 78) 7-Chloro-5-methylthiopyrazolo [1,5-a] pyrimidine-6-
After reacting 200 mg of carbonitrile (Compound No. 62) and 100 mg of furfurylamine in 5 mL of THF in the presence of 110 mg of triethylamine for about 30 minutes, about 30 mL of water was added, and the precipitated crystals were collected by filtration, washed and dried. Thus, crude crystals were obtained. The crude crystals were washed with ether to give 180 mg of 7-furfurylamino-5-methylthiopyrazolo [1,5-a] pyrimidine-6-carbonitrile (Compound No. 78) having a melting point of 110 ° C.

The compounds of the above formula (I) produced by the methods according to Synthesis Examples 1 to 4 and the above Production Methods 1 to 5
26.

[0087]

[Table 1]

[0088]

[Table 2]

[0089]

[Table 3]

[0090]

[Table 4]

[0091]

[Table 5]

[0092]

[Table 6]

[0093]

[Table 7]

[0094]

[Table 8]

[0095]

[Table 9]

[0096]

[Table 10]

[0097]

[Table 11]

[0098]

[Table 12]

[0099]

[Table 13]

[0100]

[Table 14]

[0101]

[Table 15]

[0102]

[Table 16]

[0103]

[Table 17]

[0104]

[Table 18]

[0105]

[Table 19]

[0106]

[Table 20]

[0107]

[Table 21]

[0108]

[Table 22]

[0109]

[Table 23]

[0110]

[Table 24]

[0111]

[Table 25]

[0112]

[Table 26]

Test Example 1 Pharmacological Test Method Sugar Uptake Test by L6 Cells The test compound was allowed to act on L6 cells (rat skeletal muscle-derived cells) by the following method, and the effect of promoting sugar uptake was measured. That is, L6 cells were suspended in α-Minimum Essential Medium (hereinafter abbreviated as MEM) containing 10% fetal bovine serum (hereinafter abbreviated as FBS), seeded at 5 × 10 ⁴ cells / well in a 96-well plastic plate, and placed in an incubator ( The cells were cultured at 5% carbon dioxide gas at 37 ° C.) until they proliferated over the whole well. Then, the medium is replaced with 2% FB
After switching to S-containing MEM, the cells were further cultured for 7 to 10 days (the medium was changed every two days) to differentiate into muscle cells. Subsequently, the culture solution was replaced with FBS-free MEM, and the cells were cultured for 3 hours, and then the test compound (diluted in MEM without FBS) adjusted to the treatment concentration was added to the muscle cells.
The reaction was carried out at 1 ° C. for 1 hour. Krebs-Henseleit-Ringer buffer
The cells were washed with KHR buffer, and 2-deoxy- [ ³ H] -glucose was added to the cells in KHR buffer and treated at 37 ° C. for 10 minutes. After removing the treatment solution and washing the cells with the KHR buffer, the cells are lysed with an appropriate amount of 1N sodium hydroxide solution, and [ ³ H]
Radioactivity was measured with a liquid scintillation counter (cpm). The sugar incorporation% was expressed as the radioactivity% when the test compound was treated, with the radioactivity of the control (treated only with the MEM solvent) being 100%. The compounds shown in Table 27
Treatment with 0 μg / ml and 100 μg / ml was performed to test the effect of promoting glucose uptake. As a result, it was confirmed that all the compounds tested had a sugar uptake promoting effect of at least 115% in the range of 10 μg / ml to 100 μg / ml.

[0114]

[Table 27]

Test Example 2 Drug efficacy test method Confirmation test of hypoglycemic effect Using KK-Ay / Ta mouse of type II diabetes model animal (purchased from CLEA Japan), the hypoglycemic effect of the test compound was confirmed by the following method did. Male KK fully reared and acclimated
-Ay / Ta mice were divided into 6 cases in each group, and test compounds were administered. The test compound was 0.5% carboxymethylcellulose
(Nacalai), and each compound using an oral probe
A single oral dose of 50 mg / kg (10 ml / kg) was given. At the same time, as a solvent control group, 0.5% carboxymethylcellulose was administered in the same volume (10 ml / kg) as the test compound administration group. Blood collection was performed before and after administration of the test compound and control solvent in Table 28.
After the time indicated in the above, the following method was used. The tail vein of the mouse is cut shallowly with a razor blade, 10-20 μL of blood is bled, and the blood is collected with a micropipette. Immediately take the same amount of heparin solution (20U / ml)
(Mochida Pharmaceutical) and centrifuged at 4 ° C for 5 minutes (100
00 rpm). The plasma after centrifugation was used as a sample for blood glucose measurement. The blood glucose level was measured by the glucose oxidase method, and measured using a commercially available measurement kit (Glucose CII Test Quaco, Wako Pure Chemical). The measurement was performed the day after blood collection, during which the collected plasma was stored at -20 ° C. Result is,
The blood glucose level at the time of blood collection was
The percentage was calculated as a percentage, and the hypoglycemic effect of the test compound was evaluated by comparison with the change in blood glucose (100 percentage) in the solvent control group at the time of blood collection. In addition, all the evaluation results of the hypoglycemic effect can be evaluated as having a significant difference by the Wilcoxon rank sum test (P ≦ 0.0
Five).

[0116]

[Table 28]

[0117]

The preventive or therapeutic agent for diabetes according to the present invention comprises
Since the action of promoting glucose uptake is expressed only by treating muscle cells for a short period of time, especially diabetes; impaired glucose tolerance; hyperlipidemia, vascular disorders, retinopathy, nephropathy, neuropathy,
It is useful as an agent for preventing or treating various complications such as hypertension and obesity.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61P 9/10 A61P 9/10 9/12 9/12 13/12 13/12 C07D 487/04 142 C07D 487/04 142 (72) Inventor Kazuhiro Yamamoto 2-3-1 Nishi-Shibukawa, Kusatsu-shi, Shiga Prefecture Inside the Central Research Laboratory of Ishihara Sangyo Co., Ltd. (72) Inventor Takashi Miyamoto 2-3-1 Nishi-Shibukawa, Kusatsu-shi, Shiga Prefecture F-term in the laboratory (reference) 4C050 AA01 BB05 CC08 EE03 FF03 GG04 GG06 HH01 HH02 HH04 4C086 AA01 AA02 AA03 AA04 CB06 MA01 MA04 NA14 ZA33 ZA36 ZA42 ZA70 ZA81 ZC33 ZC35

Claims (21)

[Claims] (1) Formula (I): Wherein A is a nitrogen atom or C—GＣG is CN, NO ₂ ,
SO ₂ R ³ (R ³ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group , An optionally substituted aryl group or an optionally substituted heterocyclic group), CO ₂ R ⁴
(R ⁴ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, An optionally substituted aryl group or an optionally substituted heterocyclic group), CH
O, SO ₂ NR ^a R ^b (R ^a and R ^b are each independently
A hydrogen atom, a hydroxyl group, an alkoxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, An optionally substituted aryl group or an optionally substituted heterocyclic group, or R ^a and R ^b together form a ring)
R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an optionally substituted alkyl group, or a substituted CONR ^a R ^b (R ^a and R ^b are as defined above). A good alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, -B ¹ —R ⁵ group (B ¹ is CO, COO, O, OCO, OSO ₂ , S, SO or SO ₂ , and R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group An optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group). Amino group or -N = CR ⁶ R ⁷
(R ⁶ and R ⁷ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group,
An optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group,
Y and Z are each independently an aryl group or an optionally substituted heterocyclic group);
A nitrogen atom or C—R ⁸ ｛R ⁸ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group , optionally substituted cycloalkenyl be group, an optionally substituted aryl group, an optionally substituted heterocyclic group, -B ² -R ⁹ group (B ² is CO, COO,
O, OCO, OSO ₂ , S, SO or SO ₂ ;
⁹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, An optionally substituted aryl group or an optionally substituted heterocyclic group), an optionally substituted amino group, a cyano group or a nitro group,｝, and when Y and Z simultaneously take up C—R ⁸ , 2 R ⁸ may be the same or different; X is a nitrogen atom or C-
R ¹⁰ ｛R ¹⁰ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyl group, Good cycloalkenyl group, -B
^{A 2-} R ⁹ group (B ² and R ⁹ are as defined above), an optionally substituted amino group, a cyano group or a nitro group;
And when Y is CR ⁸ and X is CR ¹⁰ or Z is CR ⁸ , does R ⁸ and R ¹⁰ or two R ⁸ together comprise a heteroatom? May form a ring without containing the compound, or a salt thereof as an active ingredient. 2. A is CG− wherein G is CN, NO ₂ , C
O ₂ R ⁴ (R ⁴ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted A cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group),
CHO, SO ₂ NR ^a R ^b (R ^a and R ^b each independently represent a hydrogen atom, a hydroxyl group, an alkoxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group A cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, or a heterocyclic group which may be substituted, or R ^a and R ^b together form a ring. be formed a) or CONR ^a R ^b (R a and R ^b are as defined above)}; Y and Z are each independently a nitrogen atom or C-R ⁸ {R ⁸ is a hydrogen atom, a halogen Atom, alkyl group which may be substituted, alkenyl group which may be substituted, alkynyl group which may be substituted, cycloalkyl group which may be substituted, cycloalkenyl group which may be substituted; Which may be an aryl group, an optionally substituted heterocyclic group, -B ² -R ⁹ group (B ² is CO, COO, O, O
CO, OSO ₂ , S, SO or SO ₂ , and R ⁹ is
Hydrogen atom, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted An aryl group or an optionally substituted heterocyclic group), an optionally substituted amino group, a cyano group or a nitro group;
X and Z simultaneously take CR ⁸ , two R ⁸ may be the same or different; X is a nitrogen atom or C—R
¹⁰ ｛R ¹⁰ is a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted Cycloalkenyl group, -B ²
A —R ⁹ group (B ² and R ⁹ are as defined above), an optionally substituted amino group, a cyano group or a nitro group;
The preventive or therapeutic agent for diabetes according to claim 1, which is 3. R ¹ and R ² are each independently a halogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group. , optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, -B 1 ^{'-R 5} group (B ^1' is O or S
R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl Group, an optionally substituted aryl group or an optionally substituted heterocyclic group),
An optionally substituted amino group or -N = CR ⁶ R ⁷ (R ⁶
And R ⁷ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyl group. An alkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group); Y and Z are each independently a nitrogen atom or C—R ⁸ ｛R ⁸ is a hydrogen atom, a halogen atom ,
An optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, optionally substituted heterocyclic group, -B ² '-R ⁹ group (B ^2' is CO, COO,
O, OCO or S, and R ⁹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, Which is an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group), an optionally substituted amino group, a cyano group or a nitro group. For the prevention or treatment of diabetes. 4. An agent for promoting sugar uptake into muscle cells, comprising the compound according to claim 1 or a salt thereof as an active ingredient. 5. A hypoglycemic agent comprising the compound according to claim 1 or a salt thereof as an active ingredient. 6. A preventive or therapeutic agent for impaired glucose tolerance, comprising the compound according to claim 1 or a salt thereof as an active ingredient. 7. An agent for preventing or treating complications associated with diabetes, comprising the compound according to claim 1 or a salt thereof as an active ingredient. 8. The preventive or therapeutic agent according to claim 7, wherein the complications associated with diabetes are at least one selected from the group consisting of hyperlipidemia, vascular disorders, retinopathy, nephropathy, neuropathy and hypertension. 9. A prophylactic or therapeutic agent for obesity, comprising the compound according to claim 1 or a salt thereof as an active ingredient. 10. A compound of the formula (I ′): [Wherein, G represents CN, NO ₂ , CO ₂ R ⁴ (R ⁴ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, An optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group), CHO, SO ₂ NR ^a R ^b
(R ^a and R ^b are each independently a hydrogen atom, a hydroxyl group,
Alkoxy group, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted an aryl group or is an optionally substituted heterocyclic group, or R ^a and R ^b together form a ring) or CONR ^a
Be a R ^b (R ^a and R ^b are as defined above); R ¹ is a halogen atom, -O-R ⁵ group (R ⁵ is a hydrogen atom, an optionally substituted alkyl group, optionally substituted A good alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group) or be -S-R ⁵ group (R ⁵ are as defined above); R ² is a halogen atom, -O-R ⁵ group (R ⁵ are as defined above) or an optionally substituted amino group R ⁸ and R ¹⁰ are each independently a hydrogen atom, a halogen atom or an alkyl group] or a salt thereof. 11. The compound according to claim 10, wherein R ² is an amino group which may be substituted, or a salt thereof. 12. The compound or a salt thereof according to claim 10, wherein R ² is an optionally substituted amino group, and R ⁸ and R ¹⁰ are hydrogen atoms. 13. An optionally substituted amino group represented by R ² is a —NR ^c R ^d group (R ^c and R ^d each independently represent
A hydrogen atom, an —O—R ⁵ group (R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, An optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group), an optionally substituted alkyl group, an optionally substituted alkenyl group, and an optionally substituted An alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, or R
^{and c} and R ^d together form a ring).
Or a salt thereof. 14. G is CN, CO ₂ R ⁴ (R ⁴ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted Good cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group or optionally substituted heterocyclic group), CHO, SO ₂ NR ^a R ^b
(R ^a and R ^b are each independently a hydrogen atom, a hydroxyl group,
An alkoxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, or an optionally substituted A good heterocyclic group or R ^a and R ^b together form a ring) or CONRA ^′ R ^{b ′} (R ^{a ′} and R ^{b ′} each independently represent a hydroxyl group, an alkoxy group, a substituted Optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted aryl group or substituted Or ^a salt thereof, or ^a heterocyclic group, or R ^{a ′} and R ^{b ′} together form a ring). 15. A pharmaceutical composition comprising the compound according to claim 10 or a salt thereof as an active ingredient. 16. A compound of the formula (I'-1):[Wherein, R¹, R⁸, R¹⁰And G are in claim 10
As defined above] or a fused heterocyclic compound represented by
Is a process for producing the salt thereof, which is represented by the formula (VII):[Wherein, R¹And G are as described above; D is alkoxy.
L is a halogen atom, -OR
^FiveGroup, -SR^FiveOr a dialkylamino group (R ^Five
Is defined in claim 10)]]
Compound and formula (VIII):[Wherein, R⁸And R^TenIs as described above]
Reacting with a compound the fused heterocyclic ring
A method for producing a compound or a salt thereof. 17. A compound of the formula (I'-2): [Wherein, R ¹ , R ⁸ and R ¹⁰ are as defined in claim ¹⁰ above, and G ′ is CN, NO ₂ , SO ₂ NR ^a R ^b (R
is ^a and R ^b are as hereinbefore defined in claim 10) or, CONR ^a R ^b (R ^a and R ^b are fused heterocyclic compound or a salt thereof is] as defined above and is) A process for preparing a compound of the formula (VII ') [Wherein, R ¹ and G ′ are as described above, and L is a halogen atom, an —OR ⁵ group, a —SR ⁵ group, or a dialkylamino group (wherein, R ⁵ is as defined above)] And a compound represented by the formula (VIII): [Wherein R ⁸ and R ¹⁰ are as defined above]. A method for producing the above fused heterocyclic compound or a salt thereof, characterized by reacting with a compound represented by the formula: 18. A compound of the formula (I'-3): Wherein R ¹ , R ⁸ , R ¹⁰ and G are as defined in claim 10 above, and Hal is a halogen atom, or a salt thereof. 17. A method for producing the condensed heterocyclic compound or a salt thereof, comprising reacting the compound of the formula (I'-1) produced by the method of claim 16 with a halogenating agent. 19. A compound of the formula (I'-4): [Wherein, R ¹ , R ⁸ , R ¹⁰ and G are as defined in the above claim 10; R ^{5 ′} is an optionally substituted alkyl group, an optionally substituted alkenyl group, An alkynyl group, a cycloalkyl group which may be substituted, a cycloalkenyl group which may be substituted, an aryl group which may be substituted, or a heterocyclic group which may be substituted]. Or a method for producing a salt thereof, wherein the compound of the formula (I′-1) produced by the method of claim 16 and a compound of the formula (IX): R ^{5 ′} −
Reacting with a compound represented by L ′ wherein R ^{5 ′} is as described above; L ′ is a halogen atom, a methanesulfonyloxy group or a paratoluenesulfonyloxy group. A method for producing the fused heterocyclic compound or a salt thereof. 20. A compound of the formula (I'-5): Wherein R ¹ , R ⁸ , R ¹⁰ and G are as defined in claim 10; Q is a substituted amino group.
19. A process for producing a fused heterocyclic compound represented by the formula: or a salt thereof, wherein (1) a compound of the formula (I'-3) produced by the method of the above claim 18, and a compound of the formula (IV-1) : H
-Q wherein Q is as defined above, or (2) a compound of formula (I'-4) produced by the method of claim 19; ,
A method for producing the fused heterocyclic compound or a salt thereof, which comprises reacting the compound with the compound of the formula (IV-1). 21. A compound of the formula (I'-5 '): Wherein R ¹ , R ⁸ and R ¹⁰ are as defined in claim 10; G ′ is CN, NO ₂ , SO ₂ NR ^a R ^b (R
Table Q is an amino group substituted]; the ^a and R ^b wherein those defined in claim 10) or be a CONR ^a R ^b (R ^a and R ^b are as defined above) A method for producing a fused heterocyclic compound or a salt thereof,
18. A compound of formula (I'-2) produced by the method of claim 17 and a compound of formula (IV-2): L'-J
[Wherein, J is a secondary substituent of a substituted amino group represented by Q; L ′ is a halogen atom, a methanesulfonyloxy group or a paratoluenesulfonyloxy group]
And reacting the compound with a compound represented by the formula: